Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus
Jennifer A. E. Payne, Julien Tailhades, Felix Ellett, Xenia Kostoulias, Alex J. Fulcher, Ting Fu, Ryan Leung, Stephanie Louch, Amy Tran, Severin A. Weber, Ralf B. Schittenhelm, Graham J. Lieschke, Cheng Xue Qin, Daniel Irima, Anton Y. Peleg, Max J. Cryle
Abstract
The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment. Here, we present a class of antibacterial peptides with potential to act both as antibiotics and as neutrophil chemoattractants. The compounds, which we term 'antibiotic-chemoattractants', consist of a formylated peptide (known to act as chemoattractant for neutrophil recruitment) that is covalently linked to the antibiotic vancomycin (known to bind to the bacterial cell wall). We use a combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models to show that the compounds improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the formyl peptide sequence can enhance neutrophil activity through differential activation of formyl peptide receptors. Thus, we propose antibiotic-chemoattractants as an alternate approach for antibiotic development.